Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related deaths globally. However, the identification of oncogenic driver alterations involved in the initiation and maintenance of NSCLC, such as epidermal growth factor receptor mutations and anaplastic lymphoma kinase translocation, has led to the development of novel therapies that directly target mutant proteins and associated signaling pathways, resulting in improved clinical outcomes. As sequencing techniques have improved, the molecular heterogeneity of NSCLC has become apparent, leading to the identification of a number of potentially actionable oncogenic driver mutations. Of these, one of the most promising therapeutic targets is B-Raf proto-oncogene, serine/threonine kinase (BRAF). Mutations in BRAF, observed in 2%-4% of NSCLCs, typically lead to constitutive activation of the protein and, as a consequence, lead to activation of the mitogen-activated protein kinase signaling pathway. Direct inhibition of mutant BRAF and/or the downstream mitogen-activated protein kinase kinase (MEK) has led to prolonged survival in patients with BRAF-mutant metastatic melanoma. This comprehensive review will discuss the clinical characteristics and prognostic implications of BRAF-mutant NSCLC, the clinical development of BRAF and MEK inhibitors from melanoma to NSCLC, and practical considerations for clinicians involving BRAF mutation screening and the choice of targeted therapy.
Implications for practice: Personalized medicine has begun to provide substantial benefit to patients with oncogene-driven non-small cell lung cancer (NSCLC). However, treatment options for patients with oncogenic driver mutations lacking targeted treatment strategies remain limited. Direct inhibition of mutant B-Raf proto-oncogene, serine/threonine kinase (BRAF) and/or downstream mitogen-activated protein kinase kinase (MEK) has the potential to change the course of the disease for patients with BRAF-mutant NSCLC, as it has in BRAF-mutant melanoma. Optimization of screening strategies for rare mutations and the choice of appropriate agents on an individual basis will be key to providing timely and successful intervention.
摘要
非小细胞肺癌（NSCLC）一直是全球癌症相关死亡的首要原因。但目前已识别出涉及NSCLC发生和维持的致癌性驱动变异（例如表皮生长因子受体基因突变和间变性淋巴瘤激酶基因易位）, 由此催生了直接靶向突变蛋白和相关信号通路的新型治疗, 从而改善了NSCLC的临床预后。随着测序技术的进步, NSCLC的分子异质性日渐显现, 在此基础之上识别出多种具有潜在可操作性的致癌性驱动突变。其中, 最具前景的治疗靶点之一是B‐Raf原癌基因丝氨酸/苏氨酸蛋白激酶（BRAF）。2%‐4%的NSCLC携带BRAF突变, 其通常导致蛋白结构性活化, 进而激活丝裂原活化蛋白激酶信号通路。研究表明, 直接抑制突变BRAF和/或下游的丝裂原活化蛋白激酶激酶（MEK）可延长BRAF突变型转移性黑色素瘤患者的生存期。本综述围绕以下问题进行讨论：BRAF突变型NSCLC的临床特征和预后意义；从黑色素瘤BRAF和MEK抑制剂到NSCLC同类抑制剂的临床开发历程；参与筛查BRAF突变和选择靶向治疗的临床医生所需考虑的实际问题。
Keywords: B‐Raf proto‐oncogene, serine/threonine kinase; Dabrafenib; Non‐small cell lung cancer; Trametinib; Vemurafenib.
© 2017 The Authors. The Oncologist published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.